title: Rebamipide suppresses TLR-TBK1 signaling pathway resulting in regulating IRF3/7 and IFN-α/β reduction.
abstract: TANK-binding kinase 1 (TBK1) regulates the interferon regulatory factor (IRF) 3 and IRF7 activation pathways by double strand RNA (dsRNA) via Toll-like receptor (TLR) 3 and by lipopolysaccharide (LPS) via TLR4. Rebamipide is useful for treating inflammatory bowel disease (IBD). Although IBD is associated with nuclear factor-κB (NF-κB), any association with the TBK1-IRF pathway remains unknown. How rebamipide affects the TBK1-IRF pathway is also unclear. We analyzed the relationship between IBD (particularly ulcerative colitis; UC) and the TLR-TBK1-IRF3/7 pathway using human colon tissue, a murine model of colitis and human colonic epithelial cells. Inflamed colonic mucosa over-expressed TKB1, NAP1, IRF3, and IRF7 mRNA compared with normal mucosa. TBK1 was mainly expressed in inflammatory epithelial cells of UC patients. The expression of TBK1, IRF3, IRF7, IFN-α and IFN-β mRNA was suppressed in mice given oral dextran sulfate-sodium (DSS) and daily rectal rebamipide compared with mice given only DSS. Rebamipide reduced the expression of TBK1, IRF3 and IRF7 mRNA induced by LPS/dsRNA, but not of NF-κB mRNA in colonic epithelial cells. Rebamipide might suppress the TLR-TBK1 pathway, resulting in IRF3/7-induction of IFN-α/β and inflammatory factors. TBK1 is important in the induction of inflammation in patients with UC. If rebamipide represses the TLR-TBK1 pathway, then rectal administration should suppress inflammation of the colonic mucosa in patients with UC.
authors.affiliation: Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Ogasawara
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Itoh
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tokudome
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kondo
authors.forename: Yoshitsugi
authors.initials: Y
authors.lastname: Ito
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
authors.forename: Kunio
authors.initials: K
authors.lastname: Kasugai